Objective Lupus flares when genetically predisposed people encounter appropriate environmental agents. Current evidence indicates that the environment contributes by inhibiting T cell DNA methylation, causing overexpression of normally silenced genes. DNA methylation depends on both dietary transmethylation micronutrients and Erk-regulated DNA methyltransferase 1 (Dnmt1) levels. We used transgenic mice to study interactions between diet, Dnmt1 levels and genetic predisposition on the development and severity of lupus. Methods A doxycycline-inducible Erk defect was bred into lupus-resistant (C57BL/6) or lupus-susceptible (C57BL/6xSJL) mouse strains. Doxycycline treated mice were fed a standard commercial diet for eighteen weeks then switched to diets supplemented(MS) or restricted(MR) intransmethylation micronutrients. Disease severity was assessed by anti-dsDNA antibodies, proteinuria, hematuria and histopathology of kidney tissues. Pyrosequencing was used to determine micronutrient effects on DNA methylation. Results Doxycycline induced modest levels of anti-dsDNA antibodies in C57BL/6 mice and higher levels in C57BL/6xSJL mice. Doxycycline-treated C57BL/6xSJL mice developed hematuria and glomerulonephritis on the MR and standard but not the MS diet. In contrast C57BL/6 mice developed kidney disease only on the MR diet. Decreasing Erk signaling and methyl donors also caused demethylation and overexpression of the CD40lg gene in female mice, consistent with demethylation of the second X chromosome. Both the dietary methyl donor content and duration of treatment influenced methylation and expression of the CD40lg gene. Conclusions Dietary micronutrients that affect DNA methylation can exacerbate or ameliorate SLE disease in this transgenic murine lupus model, and contribute to lupus susceptibility and severity through genetic/epigenetic interactions.

Humans and mice with sickle cell disease (SCD) have rigid red blood cells (RBCs). Omega-3 fatty acids, such as docosahexanoic acid (DHA), may influence RBC deformability via incorporation into the RBC membrane. In this study, sickle cell (SS) mice were fed natural ingredient rodent diets supplemented with 3% DHA (DHA diet) or a control diet matched in total fat (CTRL diet). After 8 weeks of feeding, we examined the RBCs for: 1) stiffness, as measured by atomic force microscopy; 2) deformability, as measured by ektacytometry; and 3) percent irreversibly sickled RBCs on peripheral blood smears. Using atomic force microscopy, stiffness is increased and deformability decreased in RBCs from SS mice fed CTRL diet compared to wild-type mice. In contrast, RBCs from SS mice fed DHA diet had markedly decreased stiffness and increased deformability compared to RBCs from SS mice fed CTRL diet. Furthermore, examination of peripheral blood smears revealed less irreversibly sickled RBCs in SS mice fed DHA diet as compared to CTRL diet. In summary, our findings indicate that DHA supplementation improves RBC flexibility and reduces irreversibly sickled cells by 40% in SS mice. These results point to potential therapeutic benefits of dietary omega-3 fatty acids in SCD.

The C57BL/6 mouse strain fed a high‐fat diet (HFD) with ~60% of kcals from fat (lard) is an established rodent model of diet‐induced obesity. To determine if there is an ideal start age or diet composition which enhances development of obesity phenotypes, two HFD patterns were initiated at 3, 6, or 9 weeks of age. The HFD varied in fat (F, amount and type) and sucrose (S), abbreviated as follows in percent energy: 45F30S (milkfat) and 60F10S (lard). The HFD fed mice were compared to mice fed a purified low‐fat control (17F7S). Body weight and food disappearance were assessed once weekly in the nine groups of mice (n=15–16/group). Half of the mice underwent a glucose tolerance test at 17 weeks of age and had serial DEXA measurements performed at 9, 15, and 19 weeks of age. Within 3–4 weeks, mice started on the HFD were significantly heavier than controls irrespective of the age the diet was started. Upon initiation of HFD at 6 or 9 weeks, mice rapidly increased their rate of weight gain and attained similar weight compared to 3 week HFD mice with the exception of 9 week 60F10S which failed to catch‐up by 19 weeks. Calculated energy intake was greatest in the first week following HFD initiation. Intake tended to be higher throughout the remainder of feeding in all HFD groups. DEXA measurements at 9 weeks of age revealed animals fed HFD for 3 or 6 weeks showed similar percent fat that was approximately double controls (17 vs 32%). By 15 and 19 weeks of age all HFD groups showed a doubling of percent fat compared to controls (22 vs 44%‐15 wk and 25 vs 46%‐19 wk). Independent of start age, GTT at 17 weeks revealed HFD fed mice were glucose intolerant compared to control animals with a 60% increase in glucose area under the curve. In summary, these two HFD diet patterns produced similar obesity phenotypes. The age at which these HFD were initiated did not impact the percent fat or glucose tolerance measured after 8–14 weeks of feeding.

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